Herpes viruses have developed strategies to counteract host defenses so as to allow viruses to infect cells and result in a latent or persistent infection. The goal of this project is to identify and determine the function of herpes virus proteins that interact with host cell proteins to influence the course of infection. These proteins may allow us to identify new molecules that are important in the human immune system. Epstein-Barr virus (EBV) infects B lymphocytes, causes infectious mononucleosis, and is associated with certain human tumors. EBV encodes a protein termed BARF1 which acts as an oncogene. In collaboration with investigators at Immunex Corporation, we found that the BARF1 protein encodes a soluble receptor for a cytokine called colony stimulating factor 1 (CSF- 1). While the normal receptor is a membrane bound protein, the viral protein is secreted from virus-infected cells. EBV BARF1 can inhibit the ability of CSF-1 to induce proliferation of macrophages. Since macrophages produce a number of proteins that can inhibit EBV infection, EBV BARF1 may allow the virus to persist in the body despite a vigorous immune response. Programmed cell death (apoptosis) is an antiviral defense mechanism used by the host to eliminate virus-infected cells. Some viruses encode proteins that interfere with signaling pathways for apoptosis. We have identified a family of proteins encoded by DNA viruses, that inhibit programmed cell death. This family includes proteins encoded by the Kaposi sarcoma herpesvirus, molluscum contagiosum virus, and bovine herpes virus 4. The viral proteins are homologs of a cellular protein, c-FLIP, that also inhibits programmed cell death. We have shown that several of the viral proteins can bind to other cellular proteins that normally mediate apoptosis; by binding to the cellular proteins, the viral proteins inhibit apoptosis. This may allow virus-infected cells to escape apoptosis.